Final Exam Flashcards

Question

Celecoxib

Answer 1

- almost 100% selective for COX2 ‘in vivo’ - approved for osteoarthritis - poor to negligible analgesia - no effect on platelets/bleeding - far less likely to cause GI ulceration & bleeding than non-selective NSAIDs, if gastric lesions are not already present — **COX2 products involved in healing gastric ulcers** Concerns: - reduced blood flow to kidneys = reduced renal function; intravascular clotting = increased risk of stroke & MI - w/ chronic use in osteoarthritis and rheumatoid arthritis, not with acute or intermittent use

Answer 2

- regular non-selective NSAIDs inhibits synthesis of all COX1 & COX2 products = inhibition of TXA2 has a greater effect than inhibition of PGI2 — in favour of bleeding - coxibs inhibit only COX2 = less PGI2 produced — in favour of intravascular coagulation (hence, stroke & MI) **effects are only observed after prolonged use (>18 months)**

Answer 3

- antipyretic, analgesic - little peripheral activity = negligible anti-inflammatory effect & no effect on blood clotting **no longer considered an NSAID** MOA: centrally inhibits PG synthesis

Answer 4

Two mechanisms: 1. Nuclear pathway promotes protein production, inhibiting EGFR 2. Cytoplasmic pathway activates proteins, inhibiting EGFR **plasma membrane receptors = rapid effects** MOA: indirectly inhibit PA2 —> inhibits synthesis of AA —> inhibits synthesis of PGs & leukotrienes —> inhibits inflammation & essentially all WBC functions **more profound effect than NSAIDs**

Answer 5

- stimulate hepatic glucose syn. from amino acids & lipids - inhibit glucose uptake by muscle & adipose - stimulate fat breakdown in adipose - mobilize amino acids from non-hepatic tissues

Answer 6

Ca2+, formation, wound, immune

Answer 7

Osteoporosis

Answer 8

Absorption: oral; IM / SQ; intra-articular; topical Distribution: carried in blood via albumin & transcortin Metabolism: hepatic ADRs possible ~ some activated in liver: - cortisol —> hydrocortisone - prednisone —> prednisolone Excretion: urine / feces

Answer 9

Serious AEs — usually only seen after ~2 weeks of continuous, dose-dependent therapy **risk of AEs related to duration AND dose** Numerous, possibly severe if not used properly: • Increased appetite, thirst, & urination • Impaired wound healing/thinning of skin • Hypertension (mineralocorticoid activity, RAS activation, etc.) • Edema • Negative calcium balance (osteoporosis) • Gastric ulcers • Psychoses / euphoria • Infection • 'Centripetal' fat distribution & hair loss

Answer 10

1. Empirical use, except for replacement therapy → alleviation of a patient's symptoms until initial insult has been resolved (if possible) 2. Consider risks / benefits in that patient — goal = toleration of condition, not complete relief 3. Dose very dependent on disease/patient → trial & error — use smallest possible dose 4. Re-evaluate periodically — gradually reduce dose to minimum acceptable 5. Generally, even large single doses are harmless — crisis situation 6. < 1 week unlikely to be harmful 7. Time & dose related to toxicity (> 1 week) 8. With chronic use, abrupt cessation → adrenal insufficiency **MUST wean patient off drug GRADUALLY** **Hypoadrenocorticism secondary to abrupt glucocorticoid cessation** ~ may or may not be as severe as Addison's disease, depending on the drug ~ drugs such as cortisone, prednisone, and prednisolone, which have some mineralocorticoid activity, will suppress the patient's aldosterone levels during therapy ~ aldosterone levels may be inadequate following abrupt cessation of the glucocorticoid, resulting in: — Na+ and water loss → low BP — K+ retention → arrhythmias **these effects may be fatal**

Answer 11

- provide early to minimize damage from inflammation; patient should exercise affected joints moderately = slow disease progress - caution regarding “masking” of pain; patients may overuse & injure inflamed joints (ex. athletes) - hypersensitivities for oral / inhaler; use injectable drug for anaphylaxis

Answer 12

To prevent prolonged hemorrhage & spontaneous thrombosis; remain localized **involves temporally overlapping stages**

Answer 13

- platelet activators - procoagulants - vasoconstriction - fibrinolytic inhibitors

Answer 14

- platelet inhibitors - anticoagulants - vasodilators - fibrinolytic activators

Answer 15

1. Vasospasm (vasoconstriction) 2. Platelet response 3. Coagulation phase 4. Clot dissolution (fibrinolysis)

Answer 16

- damaged vessel immediately constricts, reducing blood flow = limits blood loss - response occurs as a result of sympathetics & local factors (e.g. TXA2, endothelin) = initiates myogenic properties in vessel wall *smooth muscle contraction*

Answer 17

- platelets adhere to exposed collagen of damaged endothelium and to each other = platelet plug releases chemical mediators (e.g. TXA2, ADP) **recruits more platelets, promotes vasoconstriction, initiates coagulation cascade**

Answer 18

- involves sequential conversion of inactive proteins into catalytically active proteases; divided into intrinsic (in vitro) & extrinsic (in vivo) pathways (converge at factor X activation — common pathway) - extrinsic pathway: coagulation cascade initiated at site of injury by expression of TF complexing with factor VIIa = conversion of fibrinogen to fibrin by thrombin — protein matrix reinforces clot

Answer 19

- involves proteolytic actions of plasmin bound to clot **needed for wound healing & vessel flow restoration**

Answer 20

- platelet deficiency (thrombocytopenia; von Willebrand’s) - clotting factor deficiency (single factor (hemophilia - VIII, IX); multiple factors (vitamin K deficiency)) - fibrinolytic hyperactivity

Answer 21

- vitamin K - antifibrinolytic agents - blood products (replacement factors) - others*

Answer 22

2 natural form exist: vitamin K1 (phytonadione — foods); vitamin K2 (menaquinone — intestinal bacteria) - available for oral & parenteral use; IV route (give slow; anaphylaxis); SC injection (preferred route) - considered very safe; fat-soluble (requires bile salts for intestinal absorption) MOA: confers biological activity to factors II, VII, IX, X via post-translational modification - requires ~6-12 hours for new factors & clinical effects Uses: anticoagulant toxicity; vitamin K deficiency; prevent hemorrhagic disease (newborns)

Answer 23

**Plasmin lyses fibrin and fibrinogen by attaching to lysine binding sites** *Aminocaproic acid (Amicar)* - synthetic agent similar to lysine - MOA: blocks lysine binding site; competitively inhibits plasmin action on fibrin **incomplete lysis can lead to thrombi formation** - Uses: bleeding from fibrinolytic therapy; adjunct therapy-hemophiliacs

Answer 24

**Deficiencies in plasma coagulation factors can cause bleeding; spontaneous when key factors < 5-10% of normal levels** - examples: factor VIII deficiency (hemophilia A/classic hemophilia); factor IX deficiency (hemophilia B/Christmas disease) — treatment? concentrated plasma factors!

Answer 25

- transiently increases factor VIII activity in mild hemophilia or von Willebrand’s disease - available as tablets, injectable or nasal spray (high doses)

Answer 26

- low MW, strongly basic (cationic) protein produced by recombinant technology - used to treat heparin overdoses by binding & neutralizing its coagulant effects *more effective against large MW heparin molecules in unfractionated heparins vs. low MW heparins* - give IV slowly to avoid AEs (includes collapse) - monitor patient — high doses can produce anticoagulant effects

Answer 27

- essential nutrients - growth factors

Answer 28

- to provide components for RBCs and hemoglobin - to stimulate bone marrow formations of RBCs

Answer 29

- forms complex w/ oxygen in hemoglobin & myoglobin (transport) - used in treatment or prevention of disorders associated w/ deficiency (chronic blood loss in adults; prevention of newborn iron deficiency; anemia from chronic renal failure; inadequate iron absorption from GI tract) - oral (ferrous salts) or parenteral (iron dextrans via injection) administration

Answer 30

- essential for DNA synthesis - examples: folic acid; vitamin B12 (cyanocobalamin) *administered alone or in multivitamin preparations; oral or injected*

Answer 31

- glycoprotein hormone produced by kidney in response to hypoxia **primarily used in cases of chronic anemia due to reduced EPO in CRF; has been used in anemia of other causes (AIDs, cancers, elective surgeries)** *iron supplementation advised in combination* MOA: stimulates proliferation & differentiation of red cell progenitors & release of reticulocytes - following treatment: increase in hematocrit & hemoglobin in 2-6 weeks AEs: hypertension, thrombosis

Answer 32

- granulocyte colony stimulating factor MOA: stimulates proliferation & differentiation of myeloid progenitor cells (neutrophil lineage) - activates polymorphic neutrophils (increases their life in circulation) - mobilizes hematopoietic stem cells in circulation *important source of cells for transplantations following high dose chemotherapy; improves stem cell engraftment & recovery* Uses: indicated for chemotherapy-induced neutropenia — ameliorates myelosuppression of neutrophils (no improvement in survival noted)

Answer 33

MOA: stimulates myeloid, lymphoid & megakaryocyte progenitor cells in conjunction w/ growth factors - used to treat thrombocytopenia

Answer 34

Fibrin-rich; contains large # of RBCs; occurring in veins

Answer 35

Platelet-rich; occurring in arteries

Answer 36

Prothrombic factors

Answer 37

- endothelial injury (local vessel) - circulatory stasis - altered blood coagulability (hyperactivity of hemostatic mechanisms; hypoactivity of fibrinolytic mechanisms)

Answer 38

- systemic anticoagulants - antithrombotic drugs - fibrinolytic drugs

Answer 39

- prevents pathologic thrombosis - limits reperfusion injury & bleeding - allows normal response to vascular injury

Answer 40

- mixture of sulfated mucopolysaccharides; highly negatively charged MOA: enhances (accelerates 100-fold) action of antithrombin III (forms heparin-ATIII complex); AT-III inhibits activated clotting factors, especially thrombin IIa and Xa — “suicide substrate” Uses: primarily used in initial treatment of thrombosis and thromboembolic disease; prevents thrombi from enlarging & new thrombus formation (*does not lyse existing thrombus*) *rapid onset of action = acute anticoagulant (oral - concurrently)* **used in venous thrombosis, pulmonary embolism, unstable angina, atrial fibrillation, acute MI & various cardiovascular surgeries** AEs: bleeding tendencies & possible thrombocytopenia *monitor aPTT - 1.8-2.5 X normal mean*; protamine sulfate can neutralize heparin overdose

Answer 41

- low MW heparin - inactivate factor Xa well, but not thrombin (IIa) - used more commonly due to advantages (less bleeding tendencies possible, protamine sulfate less active against LMW heparins (reversible), less risk of thrombocytopenia, improved pharmacokinetics (can give SC; longer half-life))

Answer 42

- oral / injectable anticoagulant - used as chronic preventative anticoagulant therapy; dosing usually begun w/ heparin administration - monitor using INR (PT/mean PT) — increase to 2.0-3.0 MOA: antagonizes vitamin K actions, reducing clotting factors (II, VII*, IX and X) — clotting not affected until existing factors used *6 hrs half-life Toxicities: bleeding tendencies (can treat w/ vitamin K1); serious bleeding (requires fresh blood/plasma); crosses placenta (heparin does not cross)

Answer 43

Rivaroxaban (Xarelto) MOA: inactivates factor Xa directly; does not interact w/ ATIII and no thrombin activity - prevention of stroke secondary to atrial fibrillation - prevention & treatment of deep venous thrombosis & pulmonary embolism

Answer 44

- more specific inhibition of thrombin w/ negligible effects at factor Xa Bivalirudin (Angiomax) - derived originally from lepirudin (medicinal leeches); now prepared synthetically; given by IV injection MOA: binds and inhibits thrombin via its active site & exosite Dabigatran (Pradaxa) - given orally; prodrug MOA: binds and inhibits thrombin via its active site

Answer 45

Platelet activators - outside platelet acting on its membrane (collagen, thrombin) - produced within granules that act on platelet membrane once released (ADP, 5-HT, TXA2) - produced in platelet and act within it (cyclooxygenase, cAMP, cGM and Ca2+)

Answer 46

Clopidogrel* (Plavix), Prasugrel* (Efient), Ticagrelor (Brilinta)** *irreversible inhibitors; prodrug (must be activated by liver P450 metabolism) **competitive inhibitor of P2Y12 receptor - indicated to reduce and prevent recurrence of stroke and MI in affected individuals; agents are fairly safe MOA: reduces aggregation by inhibiting ADP pathways - acts as P2Y12 receptor antagonists (prevent binding of ADP to receptors); may be synergistic w/ aspirin (different MOAs)

Answer 47

Glycoprotein IIb/IIIa (platelet surface integrin receptor for fibrinogen) — receptor expression activated by thrombin, collagen, ADP, epinephrine & TXA2; once activated, binds & anchors platelets to each other Abciximab (REOPRO) MOA: Fab fragment of humanized monoclonal antibody directed against IIb/IIIa platelet receptor; irreversibly inhibits platelet aggregation - indicated in percutaneous angioplasty associated w/ coronary thrombosis - major toxicity: possible bleeding tendencies Eptifibatide (Integrillin) MOA: synthetic peptide reversibly inhibits IIb/IIIa receptor & platelet aggregation - similar uses & AEs to abciximab

Answer 48

MOA: rapidly lyse thrombi by activating plasmin from clot-bound plasminogen (ideally local fibrinolysis only) Tissue plasminogen activator; t-PA or alteplase (Activase) - serine protease that binds fibrin (produce by endothelial cells) - preferentially activates clot-bound plasminogen; limits activation of systemic plasmin - *fairly short half-life = constant infusion* - uses: treatment of coronary thrombosis in acute MI; deep venous thrombosis; acute ischemic stroke; pulmonary embolism - toxicities: bleeding tendencies Tenecteplase (TNKase) - engineered variant of t-PA w/ similar efficacy & possibly less bleeding - *longer half-life = single bolus injection*

Answer 49

Cholesterol/lipid plaques in coronary arteries from many lipid disorders

Answer 50

Increase; decrease; decrease; decrease

Answer 51

Lipoproteins

Answer 52

Coronary artery disease; stroke; peripheral artery disease

Answer 53

- these compounds are structural analogs of HMG-CoA (enzyme that mediates early steps of hepatic sterol synthesis) Lovastatin, Rosuvastatin (Crestor) - most effective & best tolerated drugs for therapy of hyperlipidemias; used as monotherapy (high efficacy); may be used w/ other drug classes Pleiotropic effects: may contribute to reduction in cardiovascular morbidity & mortality (decreased inflammation (reduction in C-reactive protein); reversal of endothelial dysfunction (improved vasodilation to NO); decreased thrombosis; increase atherosclerotic plaque stability) MOA: partially inhibit HMG-CoA reductase (decreases hepatic cholesterol levels) - have high hepatic first-pass effect - induce an increase in high affinity LDL receptors (principally in the liver) — increases LDL clearance; decreases plasma LDLs Toxicities: possible increase in liver enzymes & risk of teratogenic effects (contraindicated in pregnancy); drug interactions possible = altered CYP450’s

Answer 54

- one of the oldest drugs used to treat hyperlipidemias - rapid-release & slow-release tablets - acts as a vitamin B3 when converted to NAD **unconverted niacin produces lipid lowering effects** MOA: inhibits VLDL production & secretion = decreases LDL levels via liver effects; decreases adipose lipoprotein lipase activity = decrease hepatic production of VLDL’s - best agent for raising HDL’s Toxicities: cutaneous flushing & pruritus can occur (mediated by PG release (can be alleviated w/ aspirin or another NSAID)); GI distress & ulcers possible

Answer 55

Cholestryamine, Colestipol (Colestid) - one of the oldest & safest drugs used to treat hyperlipidemias - very large highly positively charged (cationic) resins - usually used as second agents if statins alone are ineffective - available as granule packets or tabs (oral); taken w/ meals (bile secretion is highest); insoluble in water (not absorbed by GI tract) MOA: bind negatively charged bile acids in GI tract lumen (prevents re-uptake in jejunum/ileum; increased bile acid synthesis = decreased liver cholesterol concentration = increased hepatic LDL receptors & increased LDL uptake & clearance from plasma Toxicities: constipation & bloating (common); drug interactions possible = positive charges on resins

Answer 56

Gemfibrozil (Lopid) MOA: unclear — acts as ligand for nuclear transcription receptor PPAR-alpha* *found largely in liver, skeletal muscle; increases lipoprotein lipase levels in muscle = decrease in VLDL (and its secretion); modest decrease in LDL’s & moderate increase in HDL’s occur - considered safe & can be used in combination w/ other lipid lowering agents AEs: GI discomfort (most common); increases risk of cholesterol gallstones

Answer 57

Ezetimibe (Zetia) MOA: inhibits intestinal absorption of phytosterols & cholesterol (targets transport protein in jejunal enterocytes used to uptake cholesterol present in micelles); decreases LDL levels (hepatic LDL receptors increase as LDL’s removed from plasma) — both dietary & biliary cholesterol affected - excreted in bile following absorption & metabolism - used primarily as an adjunct w/ statins - appears very safe - inhibitors of bile acid absorption may inhibit ezetimibe absorption

Answer 58

Surgery, radiation, chemotherapy

Answer 59

Cancers of epithelial cells lining the surface of organs

Answer 60

Cancers of muscle, bone, cartilage, fat, connective tissue

Answer 61

Group of blood cancers, usually originate in bone marrow resulting in underdeveloped blood cells

Answer 62

Group of cancers that develop from lymphocytes

Answer 63

Cancers that develop from precursor cells or embryonic tissue

Answer 64

Carcinomas - epithelial cells = site of extensive cell proliferation & frequent exposure to chemical/physical damage

Answer 65

A single aberrant cell = genetic mutation or epigenetic mutation

Answer 66

- mutation/epigenetic alteration rate - selective advantage - proliferation rate - invasiveness

Answer 67

- DNA proofreading/repair genes - genes maintaining chromosomal integrity - oncogenes - tumour suppressor genes

Answer 68

- gain of function - mutation in gene regulating cell growth = increase mitosis - examples: hormones/growth factors, receptors, cell signalling molecules, transcription factors

Answer 69

- loss of function - mutation in gene that normally suppresses mitosis & cell growth, induces apoptosis or DNA repair - examples: transcription factors/repressors

Answer 70

- larger tumours require oxygen & nutrients - tumours secrete growth factors to induce blood vessel growth

Answer 71

*least understood & most feared aspect of cancer* - detachment of cells from parent tumour - entry into blood vessel - exit circulation - survival & proliferation in new environment

Answer 72

- design of effective treatments - understanding lack of drug response

Answer 73

S-phase *some effective during M-phase*

Answer 74

G₀ phase

Answer 75

% dividing cells sensitive to chemotherapy

Answer 76

Early metastases

Answer 77

Fast-growing

Answer 78

Synchronize

Answer 79

First-order (constant %) *10⁹ to 10⁵ = 4 log kill (difference of 10000 times)*

Answer 80

1. Cure requires death of ALL tumour cells 2. Drugs kill constant proportion of tumour cells 3. Tumours detected later = prolonged treatment 4. Drugs have narrow therapeutic index 5. Drug combinations = increase effectiveness & decrease AEs 6. Intermittent high-dose therapy = more effective 7. Adjuvant therapy may decrease metastases and/or AEs

Answer 81

- nature of cancer (type, stage at diagnosis, cell-cycling phase, growth rate, heterogeneity) - pharmacology (time of initiation & timing of treatment, drug combination) - patient (general health, tumour blood supply, immune status) - failure of anticancer drugs (lack of specificity (side effects, dosage limitations), cancer exhibits/develops resistance)

Answer 82

- bone marrow (myelosuppression) - GI tract (vomiting, nausea, diarrhea) - hair follicle (alopecia) - reproductive tract (decreased sperm, menopause, teratogenicity) - secondary carcinogenicity

Answer 83

- natural (some neoplasm cells inherently resistant) - acquired (mutation —> resistance development) - multidrug resistance (cells express resistance mechanism that affects multiple drugs (e.g. p-glycoprotein pumps drug out of cell)

Answer 84

- most often given in combination (synergistic, different MOAs & resistance) - drugs should be given as frequently & as close to the maximal effective dose as possible

Answer 85

- generally based on body surface area - PKs, drug interactions & impact on liver, kidney & immune system taken into account

Answer 86

- type/stage of cancer - health of patient (renal/hepatic function, bone marrow reserve, concurrent medical problems) - desire to undergo difficult/dangerous treatment - ability to cope w/ side effects - pre-treatment screening

Answer 87

- long-term gain vs. risk - probability of successful treatment vs. quality of life

Answer 88

MOA: transfer alkyl group to cellular constituents; major site of action in DNA — attaches to N7 and/or O6 of guanine - agents can be monofunctional (alkylate single DNA strand) or bifunctional (alkylate at two locations; cross-link) *proliferating cells are more sensitive*

Answer 89

Alkylsulfonates Methyl/ethylenimines Nitrogen mustards (cyclophosphamide) Nitrosoureas Platinum compounds* (cisplatin) Triazenes *technically not alkylating agents, but also bind N7 & cross-link DNA

Answer 90

- most commonly used alkylating agent - administered IV or orally; lipid soluble - prodrug; activated by cytochrome P450 - broad spectrum: used alone or in combo w/ other drugs to treat neuroblastomas, lymphomas, leukemias & colon, breast, ovarian, small cell lung & testicular cancers *less toxic than some alkylating agents due to cellular metabolism of aldophosphamide by ALDH* AEs: dose-dependent GI disturbances, bone marrow suppression, immunosuppression, hair loss, hemorrhagic cystitis (acrolein accumulation); increased risk of sterility, menopause, cancer Resistance occurs due to… - reaction w/ other cellular constituents - increase in metabolism (ALDH, GST) - increase in DNA repair (e.g. cancer cells w/ high levels of MGMT less susceptible)

Answer 91

- inorganic metal: covalently binds N7 & O6 of guanine; interacts with cytosine and adenine - administered IV - particularly effective for testicular, bladder, ovarian cancer; used to treat lymphomas, sarcomas, and lung carcinomas AEs: bone marrow suppression, anemia, GI distress (one of most emetogenic chemotherapies), nephrotoxicity, electrolyte imbalances, neurotoxicity (hearing loss, peripheral neuropathy) Resistance occurs due to… - decreased access to DNA - increased DNA repair

Answer 92

- antibiotics extracted from soil microbe (*streptomyces*) — has anti-tumour activity MOA: form tight drug-DNA interactions (DNA intercalation); free radical DNA damage = DNA unwinding, impaired synthesis, single & double strand breaks — interfering w/ cell proliferation

Answer 93

- administered through variety of routes (IV, IM, SC), typically in combo with other drugs to treat lymphomas & cervical, ovarian & testicular cancer MOA: forms DNA-bleomycin-Fe(II) complex that interacts w/ oxygen (oxidation = free radicals; DNA strand breakage & damage of other cellular constituents) AEs: pulmonary fibrosis, anaphylaxis, GI disturbances, alopecia Resistance occurs due to… - increased DNA repair - increased drug efflux - increased expression of antioxidants or bleomycin hydrolase

Answer 94

Cyclophosphamide, methotrexate, fluorouracil (CMF) *refer to image*

Answer 95

- affect cell proliferation by interfering with DNA & RNA synthesis (interfere with the availability of purines & pyrimidines) *most effective in S-phase of cell cycle*

Answer 96

Folate antagonists (methotrexate) Pyrimidine analogues (5-fluorouracil) Purine analogues Sugar-modified analogues

Answer 97

- usually used in combo with other drugs for a variety of carcinomas, leukemias & lymphomas - administered orally or via injection (IV, IM, SC, IT) MOA: enter cells via active transport (folic acid inhibitor: structurally similar to folate & binds to DHF reductase); reduces purine & pyrimidine synthesis = affects RNA, DNA, and protein synthesis *methotrexate-polyglutamate metabolites retained in cells to further inhibit RNA or DNA synthesis* AEs: bone marrow suppression, GI distress, alopecia, liver damage (long-term treatment), renal damage (high dose) Resistance occurs due to… - decreased cellular uptake - increased DHF reductase expression - decreased binding to DHF reductase - increased efflux Drug interactions: - aminoglycosides decrease methotrexate absorption - NSAIDS, penicillins, cephalosporins, cisplatin, probenecid decrease methotrexate elimination

Answer 98

- primarily used to treat carcinomas of breast, skin, & GI tract (esophageal, gastric, rectal, anal) - administered IV or topically MOA: carrier-mediated transport into the cell; converted to ribosyl & deoxyribosyl nucleotide metabolites & incorporated into RNA & DNA; inhibits TS = decreased thymidine synthesis = decreased DNA synthesis AEs: bone marrow suppression, GI disturbances, (nausea, vomiting, diarrhea, ulceration), alopecia, cardiotoxicity (angina, arrhythmias), skin irritation Resistance occurs due to… - decreased cell uptake - increased 5-fluorouracil metabolism - decreased conversion to nucleotide metabolite - increased TS activity - prolonged DNA synthesis time (DNA repair) Dosing concerns: - under & overdosing - minimum effective dose & maximum tolerated dose = very close - monitoring of serum levels being investigated to maximize efficacy & minimize AEs

Answer 99

Topoisomerase inhibitors *topoisomerase II = transient ATP hydrolysis-dependent double-strand break (re-ligation of DNA); assists w/ DNA replication & transcription* - camptothecins - anthracyclines (doxorubicin) - epipodophyllotoxins - amsacrine Microtubule inhibitors *plant or synthetic alkaloids; tubulin polymerizes to form mitotic spindles; microtubule half-life decreases = spindle dissolves = cell divides* - vinca alkaloids (vincristine) - taxanes (paclitaxel)

Answer 100

- administered IV & used for leukemias & lymphomas, bladder, breast, stomach, lung, ovarian and thyroid carcinoma, tissue sarcomas & multiple myeloma MOA: intercalates w/ DNA; binds to & stabilizes topoisomerase II DNA complex to prevent re-ligation of DNA breaks; generates free radicals that damage DNA; inhibits DNA replication & transcription AEs: cardiomyopathy/heart failure, bone marrow suppression, GI disturbances, alopecia, rash/swelling of hands & feet Resistance occurs due to… - increased efflux via P-glycoprotein in cell membrane - overexpression or mutation of topoisomerase II

Answer 101

- administered IV in combo w/ other drugs to treat some carcinomas (small cell lung, breast), leukemias, lymphomas & neuroblastomas - kills cells in M-stage of cell cycle MOA: inhibits tubulin polymerization = dysfunctional spindle AEs: peripheral neuropathy, nausea, vomiting, alopecia, constipation Resistance occurs due to… - altered tubulin structure (mutations) - altered expression of tubulin isotypes - increased efflux via P-glycoprotein in cell membrane Interactions (metabolized by CYP3A4) - metabolism accelerated by some anti-convulsants & some HIV medications (nevirapine) - metabolism slowed down by some antifungals (azoles), HIV medications & grapefruit juice

Answer 102

- kills cells in M-stage of cell cycle - primarily used to treat breast, ovarian & non-small cell carcinomas & AIDS-related Kaposi’s sarcoma MOA: inhibits tubulin depolymerization = overly stable microtubules = cell cannot divide AEs: hypersensitivity, peripheral neuropathy, bone marrow suppression, alopecia, GI distress, anorexia Resistance occurs due to… - altered tubulin structure (mutations) - altered expression of tubulin isotypes - increased efflux via P-glycoprotein in cell membrane Interactions (metabolized by CYP3A4) - metabolism accelerated by some anti-convulsants & some HIV medications (nevirapine) - metabolism slowed down by some antifungals (azoles), HIV medications & grapefruit juice

Answer 103

- useful for cancers w/ steroid hormone-sensitive cells - must have steroid receptors; hormone-responsive & hormone-dependent - steroids regulate expression of genes involved in cell growth & proliferation

Answer 104

- used for immune & inflammatory suppression in variety of disorders (oral, inhalation, injection) MOA: converted to active form (prednisolone) in liver; binds irreversibly to glucocorticoid receptors; can induce apoptosis of leukemic & lymphoid cells AEs: immunosuppression, hypertension, hyperglycaemia, pancreatitis, weakness, osteoporosis, mood changes Resistance occurs due to absence or mutation of receptor

Answer 105

- SERM: selective estrogen receptor (ER) modulator - administered orally, metabolized in the liver *metabolites behave as antagonists and/or agonist of ERs, depending on the target tissue* - in estrogen-sensitive breast cancer cells: prevents ER-mediated gene expression = decreased tumour growth - currently used to treat & prevent estrogen-dependent breast cancer AEs: hot flashes, irregular periods, blood clots, reduced cognition, uterine cancer

Answer 106

Aromatase inhibitors (e.g. anastrozole); uterine cancer

Answer 107

Expression of transmembrane protein which enhances excretion of drug from cancer cell

Answer 108

- efflux pump that affects several drugs - observed in several cancers: ovarian, breast, prostate, GI tract, lung, neuroblastoma, lymphoma, leukemia - protein examples: P-glycoprotein, MDR- associated protein (multiple subtypes), lung-resistance protein, breast cancer resistance protein

Answer 109

- aka: MDR1, ABCB1, CD243 - 170 kDa transmembrane ATP-binding transporter expressed in: intestinal epithelium, hepatocytes, pancreatic, renal tubule, capillary endothelial (BBB) cells - protects cells against toxins but increased expression in tumour cells interferes w/ chemotherapeutic agents MOA: ATP & drug bind; ATP hydrolysis releases phosphate to shift position of drug = excretion *in some cancer cells* - estrogen down-regulates protein expression of P-glycoprotein - tamoxifen inhibits efflux of some drugs by P-glycoprotein - cisplatin or doxorubicin can induce P-glycoprotein expression

Answer 110

Most common: - ductal - inside milk duct (in situ or invasive) - lobular - inside milk-producing gland (in situ or invasive) Rare: - inflammatory breast cancer - male breast cancer

Answer 111

Surgery & radiation

Answer 112

Surgery and/or radiation & chemotherapy* *refer to image for several traditional combos

Answer 113

Treatment options often considered palliative > curative; some women live several years w/ metastatic breast cancer

Answer 114

- targeted therapy - angiogenesis inhibitor - approved by FDA in 2008 for use in combo w/ paclitaxel for metastatic breast cancer but withdrawn in 2011 - approved for some metastatic cancers (ovarian, kidney, colon, lung) MOA: antibody binds VEGF & acts as antagonist of VEGFR2 AEs: inhibition of blood vessel growth for maintenance & healing; hypertension, bleeding

Answer 115

- targeted therapy - approved for HER2 overexpressing breast cancer; Herceptin & paclitaxel — first-line treatment of HER2 over-expressing metastatic breast cancer AEs: fever, aches, chills, nausea, and diarrhea; cardiac dysfunction including congestive heart failure (downregulates expression of neuregulin 1 which is involved in the activation of cell survival pathways in cardiac myocytes)

Answer 116

- targeted therapy - orally administered PARP inhibitor - metastatic, HER2-negative breast cancer w/ BRCA gene mutation & already had chemotherapy (2018 approval); BRCA mutated advanced ovarian cancer (2014 approval) AEs: bone marrow suppression, GI disturbances (nausea, vomiting), anorexia, fatigue, muscle & joint pain

Answer 117

- immunotherapy - monoclonal antibody against the PD-L1 protein (blocking allows T cell to kill tumour cell); administered by slow IV infusion (every 2 to 4 weeks) - triple-negative breast cancer (does not express ER, PR and HER2) - FDA approved 2019; previously approved for some advanced, resistant and/or high PD-L1 expressing lung, bladder & liver cancers AEs: nausea, anorexia, fatigue, UTI

Answer 118

- RNA or DNA - protein coat (capsid) - lipid-rich envelope (some viruses)

Answer 119

1. Virus attaches to host cell; mediated by proteins on viral surface that bind to host membrane component 2. Virus adsorbs/enters host cell membrane 3. Virus loses enough capsid proteins (uncoating) 4. Nucleic acid becomes available for transcription into mRNAs then undergoes translation on ribosomes 5. DNA/RNA replication 6. Protein synthesis 7. Synthesized viral proteins assemble w/ viral genomes within host cell; followed by viral maturation 8. Release from cell by lysis or budding through cell membrane *antiviral drugs target these steps of viral cell cycle*

Answer 120

Acute: smallpox, influenza, rhinovirus, ebola, SARS Chronic: hepatitis B & C Latent: herpesviruses Progressive: HIV Cancer: HPV, Epstein-Barr

Answer 121

- first approved antiviral for COVID-19 (authorized w/ conditions in Canada (July 2020)) - administered IV within 7 days of infection (severe cases) MOA: blocks viral replication; metabolized to nucleoside monophosphate —> triple phosphorylated (ATP analog incorporated into newly synthesized RNA strand = premature termination of RNA product) AEs: infusion site reactions, low blood pressure, nausea, vomiting, chest tightness, respiratory failure, altered liver enzymes, back pain, echocardiogram abnormalities, renal impairment Resistance occurs due to… - mutations in viral RdRP (ATP analog not incorporated into RNA)

Answer 122

- approved for patients w/ mild-moderate symptoms at risk of severe COVID-19 (FDA - Dec 2021; Canada - Jan 2022) *Nirmatrelvir: inhibitor of Mpro (viral protease in all coronaviruses known to affect humans) —> inhibits viral polyprotein processing Ritonavir: protease inhibitor (high dose) or booster (low dose) —> slows down metabolism* AEs: change in taste, muscle aches, swollen joints, headache, blurred vision, changes in heart rate *Resistance occurs due to… - multiple mutation identified in SARS-CoV-2 Mpro near its binding site

Answer 123

MOA: inhibits neuraminidase (sialidase); sialic acid analog *neuraminidase cleaves sialic acid on surface of infected host cells to promote release of newly synthesized virus* PK: administered as prodrug, metabolized to active form in liver & GI tract AEs: nausea, GI discomfort Clinical uses: prevention & treatment of early infection by many influenza A & B sub-types Resistance occurs due to… - mutation in neuraminidase (mutant strains often less virulent) *H1N1 (2009; ~ 1 day sooner in alleviation)*

Answer 124

MOA: inhibits proton ion channel (M2) in viral envelope of influenza A —> inhibits H+ transport (necessary for proper viral protein synthesis) —> inhibits uncoating of virus —> inhibits release of viral RNA-protein complex PK: distributed throughout the body (including CNS); excreted unchanged in kidney AEs: GI disturbances, CNS disturbances (nervousness, insomnia, difficulty concentrating), renal damage in patients w/ renal insufficiency Resistance occurs due to… - mutation in M2 (~50%) Clinical uses: treatment of early infection by influenza A (not H1N1)

Answer 125

MOA: guanosine analogue activated by viral thymidine kinase (infected cells most susceptible); triphosphate acyclovir competes w/ dGTP during DNA synthesis —> DNA chain termination (inhibit viral DNA synthesis) PK: oral, IV or topical formulations; distributed throughout the body (including CNS) AEs: nausea, vomiting, diarrhea, headache, renal damage (high doses or dehydrated patients, accumulates in patients w/ renal failure) Resistance occurs due to… - altered or deficient thymidine kinase Clinical uses: treatment of active herpes infection

Answer 126

- infected w/ virus - generally symptom free - w/o treatment: clinically latency of 2-10 years

Answer 127

- symptoms (opportunistic infections) - life-span w/o treatment: 1-2 years

Answer 128

Immune cells (CD4+ T cells, macrophages, dendritic cells); CCR5 (R5-tropic); X4-tropic; 5 years

Answer 129

- first-line treatment (combo of 3 antiviral agents; typically begins w/ 2 NRTIs + 1 of NNRTI/INI/PI) *originally called HAART, now ART or cART*

Answer 130

- nucleoside reverse transcriptase inhibitor (NRTI) MOA: thymidine analogue activated/phosphorylated by mammalian kinases (viral RT not selective —> competes w/ dTTP during DNA synthesis —> DNA chain termination) *can affect human DNA polymerase at very high doses* PK: well absorbed & distributed (even in CNS); metabolized in liver (glucuronidation) AEs: bone marrow (anemia, leukopenia), CNS (headaches, seizures) Drug interactions: drugs that compete for glucuronidation (acetaminophen, benzodiazepines) Resistance occurs due to… - RT mutation, inefficient kinase activation *1/3 of patients develop resistance w/ AZT monotherapy*

Answer 131

- non-nucleoside reverse transcriptase inhibitor (NNRTI) MOA: binds to non-catalytic site & inhibits viral RT PK: well absorbed & distributed (CNS, fetus, maternal milk), metabolized in liver (oxidation (CYP3A4 & CYP2B6) —> glucuronidation) AEs: rash, hepatotoxicity Drug interactions: increased CYP3A4 —> increases metabolism of certain drugs (itself, oral contraceptives, azoles, methadone, protease inhibitors) *metabolism affected by drugs that increase or decrease CYP3A4 or CYP2B6* Resistance occurs due to… - RT mutation

Answer 132

- integrase inhibitor (INI) - initially approved by Health Canada (Nov 2007) for patients w/ ART resistant HIV; now approved for all (decreased viral load earlier in patients taking raltegravir + ART drugs, compared to those taking ART drugs alone) *effect as preventative treatment under investigation* MOA: inhibits viral integrase —> decreases transfer of viral DNA into host genome Resistance occurs due to… - viral integrase mutation **Biktarvy (fixed dose drug combination)**

Answer 133

- protease inhibitor (PI) MOA: inhibits HIV aspartyl protease (cleaves viral polyprotein into specific proteins: Phe-Pro); inhibits CYP3A4 = given at low doses as enhancer of other HIV drugs (including other PIs) PK: good bioavailability, metabolized by CYP3A4 AEs: GI disturbances, insomnia, hyperglycaemia, metabolic abnormalities (lipid levels, liver enzymes) Resistance occurs due to… - mutations in viral protease

Answer 134

- viral fusion/entry inhibitor - approved in 2007; decreased viral load in patients w/ maraviroc compared to placebo (all participants received optimized ART) - indicated for use in individuals w/ R5-tropic virus MOA: CCR5 receptor antagonist blocks binding of viral gp120 to CCR5 = prevents viral entry AEs: muscle/joint pain, cold symptoms, dizziness, GI disturbances, rare but potentially serious liver damage & allergic reactions

Answer 135

1. Macroscopic parasites - taenia species (tapeworms) - enterobius (pinworm) - pediculus (head louse) 2. Microscopic parasites - entamoeba (amebiasis) - giardiasis (beaver fever) - trichomonas (trichomoniasis) - plasmodium (malaria)

Answer 136

- cestocidal drug MOA (exact unknown): binds to parasite integumentary = focal vacuolisation; influx of Ca2+ = muscle contraction (in seconds) *impaired function of hooks & suckers at anterior end = paralysis dislodgement, death* PK: synthetic isoquinoline derivative; systemic bioavailability ~80% after oral dosing AEs: mild, transient reactions (common) — nausea, headache, abdominal discomfort Clinical uses: effective against most cestode infections (drug of choice); safe & effective as single oral dose; swallow w/o chewing (bitter taste = retching/vomiting)

Answer 137

- cestocidal drug MOA: rapidly kills scolex & segments of adult tapeworms; inhibits mitochondrial anaerobic phosphorylation of ADP = decreased ATP production PK: salicylanilide derivative; minimally absorbed from GI tract AEs: minor GI complaints rarely encountered (nausea, vomiting, diarrhea) Clinical uses: second-line choice for treatment of taenia saginata & taenia solium; single oral dose effective; cheap & readily available in many parts of the world

Answer 138

- treatment for enterobius vermicularis MOA: binds to beta-tubulin (inhibits polymerization to microtubules; inhibits parasite motility, glucose uptake, cell division) *slow kill = expelled in feces; efficacy varies w/ GI transit time* PK: benzimidazole (broad spectrum); administered orally (chewable tablets) — less than 10% absorbed AEs: short term therapy (nearly free of AEs); embryotoxic & teratogenic in animals Clinical uses: approved for pinworms (treat twice at 2-week interval)

Answer 139

- treatment for enterobius vermicularis MOA: “nicotinic anthelmintic”; acts selectively at neuromuscular junction of parasite on nicotinic acetylcholine receptors (release of acetylcholine & inhibition of acetylcholinesterase; paralysis = expulsion) PK: tetrahydropyrimidine; poorly absorbed from GI tract (activity within) AEs: mild, transient (nausea, vomiting, diarrhea) Clinical uses: approved for pinworms (treat twice at 2-week interval)

Answer 140

- treatment for pediculus capitis - synthetic pyrethroid - used on nets as mosquito repellent & insecticide; residual activity (2 weeks to 6 months); biodegraded in 1-20 weeks MOA: causes voltage-gated sodium channels to remain open = membrane depolarization = rapid paralysis PK: absorption through skin (minimal); rapidly degraded to inactive metabolites in liver; resistance to permethrin in ~50% head lice (USA) AEs: itching/mild burning sensation of scalp (inflammation of skin in response to agents; can persist for many days after lice are killed) **not significantly ovicidal; more than one application typically required (retreat at 9-10 day interval)**

Answer 141

- treatment for pediculus capitis; when permethrin fails - organophosphate MOA: irreversible inhibitor of acetylcholinestrase (accumulation of acetylcholine = rapid paralysis) PK: hydrolysed & activated by plasma carboxylesterases much faster in humans than in insects AEs: itching/mild burning sensation of scalp (inflammation of skin in response to agents; can persist for many days after lice are killed) **not significantly ovicidal; more than one application typically required (retreat at 9-10 day interval)**

Answer 142

- incorrect use of drug - hatching of lice eggs after treatment - re-infestation - drug resistance

Answer 143

**Causes the infection amebiasis** Clinical presentations: - asymptomatic intestinal infection - mild to moderate colitis - severe intestinal infection (dysentery) - ameboma (pseudotumoral lesion) - liver abscess/other extra-intestinal infection Amebicidal drugs (chemotherapy): - luminal (parasites in bowel lumen; used: i) after treatment of invasive intestinal or extra-intestinal amebic disease; ii) for treatment of asymptomatic infections) - systemic (parasites in intestinal wall & liver) - mixed (both)

Answer 144

- mixed amebicide - choice for E. histolytica (diarrhea/dysentery) — kills trophozites, not cysts) - extensive use in treatment of: giardia lamblia, trichomonas vaginalis, anaerobic cocci, anaerobic gram-negative bacilli, pseudomembranous colitis (clostridium difficile) - not reliably effective for luminal parasites; must be used w/ luminal amebicide (iodoquinol; paromomycin (aminoglycoside)) MOA: some anaerobic protozoal parasites lack mitochondrial activities for generating ATP & disposing of electrons; instead, ferredoxin-like, low redox potential, electron-transport proteins can transfer electrons to nitro groups of metronidazole (cytotoxic reduced products; bind to DNA & proteins) PK: - nitroimidazole - administered orally (readily absorbed; extensive tissue distribution (simple diffusion) - therapeutic levels in vaginal & seminal fluids, saliva, cerebrospinal fluid - metabolism (hepatic oxidation by mixed-function oxidase then glucuronylation) - excreted in urine along with metabolites - rate of plasma clearance decreases if liver function impaired - simultaneous treatment w/ inducers of hepatic mixed-function oxidase (e.g. phenobarbital) = enhanced metabolism - drugs that inhibit hepatic mixed-function oxidase (e.g. cimetidine) = prolonged excretion AEs: *nausea, *vomiting, headache, abdominal cramps, metallic taste in mouth (common); mutagenic in bacteria (best avoided in pregnant or nursing women) *if alcohol ingested simultaneously

Answer 145

- drug of choice for asymptomatic luminal infections - active against luminal stages (trophozites & cysts) - unknown MOA - side effects: rash, diarrhea, dose-related peripheral neuropathy (including rare optic neuritis) - long-term use should be avoided

Answer 146

**usually hepatic abscesses** *need to kill parasites within liver abscess, intestinal wall & lumen* - high dosage of metronidazole used to eliminate trophozoites in liver abscess & intestinal wall (not gut lumen) - followed by iodoquinol to treat intestinal infection & prevent further amebic liver abscesses

Answer 147

- most common intestinal parasitic infection of people - no tissue development - two life-cycle stages: i) trophozoite; ii) cyst - infection (ingestion of cysts) — usually in water - people-specific & zoonotic genotypes - many infections = asymptomatic; severe diarrhea can occur - drug of choice: metronidazole (dosage much lower than for amebiasis — better tolerated; typically not used for asymptomatic infections — self clearance) Risk factors for infection in humans: - ingesting contaminated drinking or recreational water - children in childcare settings - close contact w/ infected persons/animals, male-male sex - taking part in outdoor activities

Answer 148

- parasites reside in: i) female lower genital tract; ii) male urethra & prostate - does not have cyst form; trophozoite replicates by binary fission; does not survive in external environment Trichomoniasis - one of most common STIs; symptoms? — women & men - treatment: metronidazole (single (typically more effective; requires compliance) & multiple dose regimens); resistant? failure! repeat at higher doses; systemic > topical (multi focal nature of infection); simultaneous treatment of sexual partner!!

Answer 149

- caused by plasmodium falciparum*, p. vivax, p. malariae, p. ovale - drug resistance = major prophylactic & therapeutic problem **only erythrocytic parasites —> clinical illness *most serious clinical disease = death: - incubation period — generally 9-14 days; headache, pain in back & limbs, anorexia, nausea, fever, chills, anemia (young children) - cerebral malaria (severe) — usually ill for 4-5 days w/ fever, slowly lapse into coma (+/- convulsions), mortality = ~15-20% Drugs that eliminate: - liver stages = tissue schizonticides - erythrocytic stages = blood schizonticides - sexual stages = gametocides **killed by effective chemoprophylactic agents (before growing in #’s = disease) Treatment of people w/ clinical malaria: *p. falciparum & p. malariae* - one cycle of multiplication in liver (liver infection ceases < 4 weeks); elimination of erythrocytic parasites cures infection *p. vivax & p. ovale* - dormant hepatic stage (hypnozoite) — not killed by most drugs; must eliminate both erythrocytic & hepatic parasites Prevention: - resistance of parasites to drugs is only increasing; no chemoprophylactic regimen is 100% protective! - counsel people = prevent mosquito bites

Answer 150

- most common nematode infection in temperate countries - transmission: female parasite on perianal skin → pruritus (eggs → hands → ingestion); eggs sticky & can survive long periods in environment; contamination of nightclothes / bedding; eggs → wide dispersal in bedrooms / house - clinical presentation: most frequent in school age children; most infections asymptomatic; itching → irritability, incontinence, weight loss - minimise risk of infection: personal hygiene (handwashing, fingernail cleaning, regular bathing); keep bedrooms scrupulously clean & dust free; bed linen / nightclothes (change and launder frequently)

Answer 151

- chemoprophylaxis if only chloroquine-S parasites in area - treatment of chloroquine-S P. falciparum - parasite in RBC: digests host hemoglobin (essential amino acids); polymerizes heme (toxic to parasite) = hemozoin (sequestered in food vacuole) MOA: unclear; drug concentrated in parasite’s acidic food vacuole; prevent polymerization of heme = hemozoin; oxidative damage (lysis of parasite & RBC) PK: synthetic 4-aminoquinoline (oral use); rapidly absorbed and distributed to tissues; blood schizonticide; no activity against liver parasites; dealkylated by hepatic mixed function oxidase system (parent drug + metabolites → urine) AEs: minimal at low doses for chemoprophylaxis; nausea, vomiting, blurred vision (higher doses); dosing after meals decreases AEs Resistance (very common in P. falciparum) occurs due to… - mutations in membrane transporter

Answer 152

Clinical uses: recommended chemoprophylactic drug in areas w/ chloroquine-R P. falciparum; taken weekly per os MOA: blood schizonticide; no activity against hepatic stages or gametocytes; concentrated in parasite by unknown mechanism; may inhibit heme polymerization = membrane damage PK: synthetic 4-quinoline methanol (chemically related to quinine); given orally (well absorbed); extensive distribution in tissues (eliminated slowly) AEs: weekly dosing for chemoprophylaxis — neuropsychiatric toxicities (much publicity); nausea, vomiting, dizziness, sleep and behaviour disturbances; frequency of serious AEs no higher than other anti-malarials? Contraindications: history of epilepsy, psychiatric disorders *risks of mefloquine use must be balanced with risk of contracting falciparum malaria* Resistance (uncommon except in regions of Southeast Asia w/ high rates of MDR) associated with resistance to quinine and halofantrine, not chloroquine

Answer 153

Clinical uses: standard chemoprophylactic drug in areas of. Southeast Asia with MDR parasites (including mefloquine-R); administered daily per os; should not be used as a single agent (slow action); commonly used for treatment of P. falciparum in conjunction w/ quinidine or quinine (allows shorter & better tolerated course of these drugs) MOA: inhibits protein synthesis (as in bacteria); blood schizonticide; not active against liver stages AEs: infrequent GI symptoms; photosensitivity

Final Exam Flashcards

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